Ttoxicity analyses and therapeutic modification of the anti-cancer drug camptothecin

抗癌药物喜树碱的毒性分析和治疗修改

• 批准号: 282635917
• 负责人: Professor Dr. Christian Strassburg
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik I - Allgemeine Innere Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282635917?language=en
• 关键词: Ttoxicity; analyses; therapeutic; modification; anti

Colorectal cancer (CRC) is he second most diagnosed cancer in Germany leading to death of 30000 people per year. Generally, development of CRC is the outcome of interactions between environmental factors and genetic predisposition. The cellular defence system plays an essential role in the detoxification of potentially carcinogenic xenobiotics and consequently in cancer prevention. UDP-glucuronosyltransferases (UGT), as a part of the cellular defence mechanisms, catalyze the detoxification of xenobiotic substances like carcinogens and drugs.Irinotecan is used, depending on the clinical context, in a monotherapy or in combination with other cytostatic agents (FOLFIRI) for the treatment of metastatic CRC. 20-30% of the treated patients suffer from serious side effects like diarrhoea and leucopenia (up to WHO grade 4) representing the dosis limiting toxicity which affects the therapeutic and curative potential of irinotecan. Ubiquitous expressed carboxylesterases catalyze the conversion of irinotecan to its activated but also more toxic metabolite SN38. Glucuronidation by UGTs leads to inactivation and elimination of SN38 via bile and urine. In several studies, a promoter mutation in the UGT1A1 gene (UGT1A1*28) was associated with increased occurrence of serious side effects during irinotecan therapy. However, approximately 50% of the patients carrying this genotype suffered from serious side effects indicating that further factors may play a role in the prediction of diarrhoea and leucopenia. Genotyping of 105 irinotecan treated patients revealed that only the combination of 3 different polymorphisms in the UGT1A7 gene (UGT1A7*3) together with the UGT1A1*28 variant is a reliable predictor for the occurrence of irinotecan-toxocity. Against this background we want to investigate if the SNP-mediated reduced glucuronidation activity can be compensated by appropriate, non-toxic UGT1A-inducers and potentially leads to reduction of irinotecan associated toxicity. Within this project, the effects of the UGT1A-activator coffee on the occurrence and the severity of side effects during irinotecan-treatment should be analyzed. Therefore, a humanized transgenic mouse line is used which carries the above mentioned UGT1A-haplotype as a transgene. The results are compared to those of a second mouse line which carries the human UGT1A gene locus in the wild type form. Additionally, gender specific differences during a coffee attended irinotecan-therapy should be analyzed potentially offering fundamentals for not yet established gender specific therapeutic strategies.

结直肠癌（CRC）是他在德国被诊断出的第二大癌症，每年导致30000人死亡。通常，CRC的发展是环境因素与遗传易感性之间相互作用的结果。细胞防御系统在潜在的致癌异生物学的解毒中起着至关重要的作用，因此在预防癌症中起着至关重要的作用。 UDP-葡萄糖基糖基转移酶（UGT）作为细胞防御机制的一部分，催化了癌和药物等异生物生物物质的解毒。在单层或与其他细胞抑制剂（folfiri）（Folfiri）中，使用了矩阵，根据临床上下文，以irinotecan的形式进行解毒。用于转移性CRC的治疗。 20-30％的治疗患者遭受严重的副作用，例如腹泻和白细胞减少症（直至4级），代表了影响伊立替康治疗和治疗潜力的DoSIS限制毒性。无处不在表达的羧酸酯酶催化伊立替康的转化为其激活，但也更具毒性的代谢产物SN38。 UGTS葡萄糖糖化导致通过胆汁和尿液消灭SN38。在几项研究中，UGT1A1基因中的启动子突变（UGT1A1*28）与伊立替康治疗期间严重副作用的发生有关。但是，携带这种基因型的患者中约有50％患有严重的副作用，表明进一步的因素可能在腹泻和白细胞减少症的预测中起作用。 105名伊立替康治疗患者的基因分型显示，仅UGT1A7基因（UGT1A7*3）中仅有3种不同的多态性以及UGT1A1*28变体的组合是可靠的预测指标，用于出现伊立替康 - 毒性的发生。在这种背景下，我们要研究SNP介导的降低的葡萄糖醛酸化活性是否可以通过适当的，无毒的UGT1A诱导剂来补偿，并有可能导致伊立替康相关的毒性降低。在该项目中，应分析UGT1A激活咖啡对伊立替康治疗过程中副作用的严重程度的影响。因此，使用人源化的转基因小鼠系列，该系列将上述UGT1A-HAPLOTYPES作为转基因。将结果与第二小鼠系的结果进行比较，该系列携带人类UGT1A基因基因座的野生型形式。此外，应分析参加伊立替康治疗的咖啡期间的性别特定差异。